US7998969B2 - Non-nucleoside reverse transcriptase inhibitors - Google Patents

Non-nucleoside reverse transcriptase inhibitors Download PDF

Info

Publication number
US7998969B2
US7998969B2 US12/001,947 US194707A US7998969B2 US 7998969 B2 US7998969 B2 US 7998969B2 US 194707 A US194707 A US 194707A US 7998969 B2 US7998969 B2 US 7998969B2
Authority
US
United States
Prior art keywords
ylamino
pyrimidin
piperidin
dimethyl
bromo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US12/001,947
Other languages
English (en)
Other versions
US20080146595A1 (en
Inventor
Denis John Kestesz
Christine E. Brotherton-Pleiss
Minmin Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Palo Alto LLC
Original Assignee
Roche Palo Alto LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Roche Palo Alto LLC filed Critical Roche Palo Alto LLC
Priority to US12/001,947 priority Critical patent/US7998969B2/en
Assigned to ROCHE PALO ALTO LLC reassignment ROCHE PALO ALTO LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BROTHERTON-PLEISS, CHRISTINE E., KERTESZ, DENIS JOHN, YANG, MINMIN
Publication of US20080146595A1 publication Critical patent/US20080146595A1/en
Application granted granted Critical
Publication of US7998969B2 publication Critical patent/US7998969B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the invention relates to the field of antiviral therapy and, in particular, to non-nucleoside compounds that inhibit HIV reverse transcriptase and are useful for treating Human Immunodeficiency Virus (HIV) mediated diseases.
  • HIV Human Immunodeficiency Virus
  • the invention provides novel pyrimidine compounds according to formula I, for treatment or prophylaxis of HIV mediated diseases, AIDS or ARC, employing said compounds in monotherapy or in combination therapy.
  • the human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDS-related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
  • AIDS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • the HIV genome encodes protein precursors known as gag and gag-pol which are processed by the viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes.
  • NRTI nucleoside reverse transcriptase inhibitors
  • non-nucleoside reverse transcriptase inhibitors Two general classes of RTI inhibitors have been identified: nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors.
  • NRTI nucleoside reverse transcriptase inhibitors
  • CCR5 co-receptor has emerged as a potential target for anti-HIV chemotherapy (D. Chantry, Expert Opin. Emerg. Drugs 2004 9(1):1-7; C. G. Barber, Curr. Opin. Invest. Drugs 2004 5(8):851-861; D. Schols, Curr. Topics Med. Chem. 2004 4(9):883-893; N. A. Meanwell and J. F. Kadow, Curr. Opin. Drug Discov. Dev. 2003 6(4):451-461).
  • NRTIs typically are 2′,3′-dideoxynucleoside (ddN) analogs which must be phosphorylated prior to interacting with viral RT.
  • the corresponding triphosphates function as competitive inhibitors or alternative substrates for viral RT.
  • the nucleoside analogs terminate the chain elongation process.
  • HIV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by cleaving the nucleoside analog and continuing the elongation.
  • NRTIs include zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and tenofovir (PMPA).
  • NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitors which bind reversibly at a nonsubstrate-binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity (R. W. Buckheit, Jr., Non - nucleoside reverse transcriptase inhibitors: perspectives for novel therapeutic compounds and strategies for treatment of HIV infection, Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq, The role of non - nucleoside reverse transcriptase inhibitors ( NNRTIs ) in the therapy of HIV infection, Antiviral Res. 1998 38:153-179; E.
  • NNRTIs presented a low barrier to the emergence of drug resistant HIV strains and class-specific toxicity. Drug resistance frequently develops with only a single point mutation in the RT. While combination therapy with NRTIs, PIs and NNRTIs has, in many cases, dramatically lowered viral loads and slowed disease progression, significant therapeutic problems remain. (R. M. Gulick, Eur. Soc. Clin. Microbiol. and Inf. Dis. 2003 9(3):186-193) The cocktails are not effective in all patients, potentially severe adverse reactions often occur and the rapidly reproducing HIV virus has proven adroit at creating mutant drug-resistant variants of wild type protease and reverse transcriptase. There remains a need for safer drugs with activity against wild type and commonly occurring resistant strains of HIV.
  • R 1 is CO 2 -tert-Bu, CO 2 Et, phenyl C 1-3 alkyl, heteroaryl C 1-3 alkyl, phenyl or heteroaryl wherein said heteroaryl group is selected from the group consisting of pyridinyl, pyridine-N-oxide, pyrimidinyl, thiophenyl, pyrrolyl, thiazolinyl, imidazolinyl or quinolyl and said phenyl or said heteroaryl is optionally substituted with one to three groups independently selected from the group consisting of:
  • R 2 is —CN, —CH ⁇ CHCN, C 1-3 alkyl or halogen
  • R 3 is hydrogen, halogen, amino or C 1-6 haloalkyl
  • R 4 is hydrogen or amino
  • R 5a and R 5b are independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy or halogen;
  • R 6a and R 6b independently are hydrogen or together are ethylene
  • R 9 is hydrogen, C 1-3 alkyl or C 1-3 acyl
  • R 10a and R 10b are independently hydrogen, C 1-3 alkyl or C 1-6 acyl;
  • R 11a is hydrogen or halogen;
  • R 11b is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 hydroxyalkyl
  • R 12 is hydroxyl, C 1-6 alkoxy or NR 7a R 7b ;
  • X is NH or O
  • X 1 is O, S(O) p or NR 9
  • p is an integer from 0 to 2; or,
  • Compounds of formula I inhibit HIV-1 reverse transcriptase and afford a method for prevention and treatment of HIV-1 infections and the treatment of AIDS and/or ARC. HIV-1 undergoes facile mutations of its genetic code resulting in strains with reduced susceptibility to therapy with current therapeutic options.
  • the present invention also relates to compositions containing compounds of formula I useful for the prevention and treatment of HIV-1 infections and the treatment of AIDS and/or ARC.
  • the present invention further relates to compounds of formula I that are useful in mono therapy or combination therapy with other anti-viral agents.
  • the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
  • variable can be equal to any integer value of the numerical range, including the end-points of the range.
  • variable can be equal to any real value of the numerical range, including the end-points of the range.
  • a variable which is described as having values between 0 and 2 can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous.
  • R 7a , R 7b , R 8a and R 8b are hydrogen and R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 and X are as defined herein above
  • R 1 is optionally substituted phenyl and R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above
  • R 1 is optionally substituted phenyl
  • R 7a , R 7b , R 8a and R 8b are hydrogen
  • R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above
  • R 1 is phenyl substituted with CONR 7a R 7b , SO 2 NR 8a R 8b or SO 2 —C 1-6 alkyl and wherein the phenyl group is optionally further substituted with a group selected from the group consisting of (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) C 1-6 alkoxycarbonyl, (h) cyano, (i) C 1-6 acyl-amino, (j) halogen, and, (k) nitro;
  • R 5a and R 5b are CH 3 ; and, R 2 , R 3 , R 4 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , X, X 1 and
  • R 1 is phenyl substituted with CONH 2 , SO 2 NH 2 or SO 2 —C 1-6 alkyl and wherein the phenyl group is optionally further substituted with a group selected from the 9 group consisting of (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) C 1-6 alkoxycarbonyl, (h) cyano, (i) C 1-6 acyl-amino, (j) halogen, and, (k) nitro;
  • R 5a and R 5b are CH 3 ; and, R 2 , R 3 , R 4 , R 6a , R 6b and X are as defined herein above.
  • R 1 is phenyl substituted with CONH 2 , SO 2 NH 2 or SO 2 —C 1-6 alkyl and wherein the phenyl group is optionally further substituted with a group selected from the group consisting of (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) C 1-6 alkoxycarbonyl, (h) cyano, (i) C 1-6 acyl-amino, (j) halogen, and, (k) nitro;
  • R 3 is hydrogen or bromine;
  • R 4 is hydrogen;
  • R 1 is phenyl substituted at the three position with CONH 2 , SO 2 NH 2 or SO 2 —C 1-6 alkyl and wherein the phenyl group is optionally further substituted with a group selected from the group consisting of (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) C 1-6 alkoxycarbonyl, (h) cyano, (i) C 1-6 acyl-amino, (j) halogen, 24 and, (k) nitro;
  • R 5a and R 5b are CH 3 ; and, R 2 , R 3 , R 4 , R 6a , R 6b and X are as defined herein above.
  • R 1 is 3-carboxamido-phenyl, 3-aminosulfonyl-phenyl or 3-methanesulfonyl-27 phenyl
  • R 3 is hydrogen or bromine
  • R 4 is hydrogen
  • R 5a and R 5b are CH 3
  • R 2 , R 6a , R 6b and X are as defined herein above.
  • R 1 is optionally substituted phenyl C 1-3 alkyl or optionally substituted heteroaryl C 1-3 alkyl
  • R 10a and R 10b are hydrogen
  • R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , X, X 1 and p are as defined herein above.
  • R 1 is optionally substituted phenyl C 1-3 alkyl and R 2 , R 3 , R 4 , R 5 , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , X, X 1 and p are as defined herein above.
  • R 1 is phenyl C 1-3 alkyl substituted with CONR 7a R 7b , SO 2 NR 8a R 8b or SO 2 —C 1-6 alkyl and wherein the phenyl group is optionally further substituted with a group selected from the group consisting of (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) C 1-6 alkoxycarbonyl, (h) cyano, (i) C 1-6 acyl-amino, (j) halogen, and, (k) nitro;
  • R 5a and R 5b are CH 3 ; and, R 2 , R 3 , R 4 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , X
  • R 1 is phenyl C 1-3 alkyl substituted at the four position with CONH 2 , SO 2 NH 2 or SO 2 —C 1-6 alkyl and wherein the phenyl group is optionally further substituted with a group selected from the group consisting of (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) C 1-6 alkoxycarbonyl, (h) cyano, (i) C 1-6 acyl-amino, (j) halogen, and, (k) nitro;
  • R 5a and R 5b are CH 3 ; and, R 2 , R 3 , R 4 , R 6a , R 6b and X are as defined herein above.
  • R 1 is phenyl C 1-3 alkyl substituted at the four position with CONH 2 , SO 2 NH 2 or SO 2 —C 1-6 alkyl and wherein the phenyl group is optionally further substituted with a group selected from the group consisting of (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) C 1-6 alkoxycarbonyl, (h) cyano, (i) C 1-6 acyl-amino, (j) halogen, and, (k) nitro;
  • R 3 is hydrogen or bromine;
  • R 4 is hydrogen;
  • R 1 is optionally substituted heteroaryl C 1-3 alkyl or heteroaryl
  • R 4 , R 7 , R 7b , R 8a and R 8b are hydrogen and R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 9 , R 10a , R 10b and X are as defined herein above.
  • R 1 is phenyl substituted with CR 11a R 11b COR 12 and R 11a and R 11b are hydrogen and R 12 is C 1-6 alkoxy or NR 7a R 7b .
  • a method for treating an HIV-1 infection, or preventing an HIV-1 infection, or treating AIDS or ARC comprising administering to a host in need thereof a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above.
  • a method for treating an HIV-1 infection, or preventing an HIV-1 infection, or treating AIDS or ARC comprising co-administering to a host in need thereof a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above and at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists and viral fusion inhibitors.
  • the compound of formula I can be co-administered with at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitor, CCR5 antagonists and viral fusion inhibitors.
  • a method for treating an HIV-1 infection, or preventing an HIV-1 infection, or treating AIDS or ARC comprising co-administering to a host in need thereof a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 1b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above and at least one compound selected from the group consisting of zidovudine, lamivudine, didanosine, zalcitabine, stavudine, rescriptor, sustiva, viramune, efavirenz, nevirapine, delavirdine, saquinavir, ritonavir
  • the method comprises co-administering at least one compound selected from the group consisting of zidovudine, lamivudine, didanosine, zalcitabine, stavudine, emtricibine, abacavir, tenofovir, efavirenz, nevirapine or delavirdine saquinavir, ritonavir, nelfinavir, indinavir, amprenavir, atazanavir, lopinavir, enfuvirtide, maraviroc and raltegravin
  • a method for inhibiting HIV-1 reverse transcriptase in a host infected with HIV-1 comprising administering to a host in need thereof a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above.
  • a method for inhibiting HIV-1 reverse transcriptase in a host infected with HIV-1 wherein the HIV-1 reverse transcriptase with at least one mutation compared to wild type HIV-1 comprising administering to a host in need thereof a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above.
  • a method for inhibiting HIV-1 reverse transcriptase in a host infected with HIV-1 wherein the HIV-1 reverse transcriptase exhibits reduced susceptibility to efavirenz, nevirapine or delavirdine comprising administering to a host in need thereof a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above.
  • a pharmaceutical composition comprising a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 11a , R 11b , R 12 , X, X 1 and p are as defined herein above and at least one carrier, excipient or diluent.
  • R 1 is CO 2 -tert-Bu, CO 2 Et, phenyl C 1-3 alkyl, heteroaryl C 1-3 alkyl, phenyl or heteroaryl wherein said heteroaryl group is selected from the group consisting of pyridinyl, pyrimidinyl, thiophenyl, pyrrolyl, thiazolinyl, imidazolinyl or quinolyl and said phenyl or said heteroaryl is optionally substituted with one to three groups independently selected from the group consisting of: (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 haloalkyl, (d) C 1-6 haloalkoxy, (e) carboxyl, (f) CONR 7a R 7b , (g) C 1-6 alkoxycarbonyl, (h) cyano, (i) SO 2 —C 1-6 alkyl
  • alkyl denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms.
  • lower alkyl denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms.
  • C 1-3 alkyl refers to an alkyl composed of 1 to 3 carbons.
  • alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • alkyl When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group.
  • phenylalkyl denotes the radical R′R′′—, wherein R′ is a phenyl radical, and R′′ is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical.
  • arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, and 3-phenylpropyl.
  • arylalkyl or “aralkyl” are interpreted similarly except R′ is an aryl radical.
  • (hetetero)arylalkyl” or “(hetetero)aralkyl” are interpreted similarly except R′ is optionally an aryl or a heteroaryl radical.
  • An “alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents.
  • “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth.
  • alkylene denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH 2 ) n ) or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., —CHMe- or —CH 2 CH(i-Pr)CH 2 —), unless otherwise indicated.
  • the open valences of an alkylene group are not attached to the same atom.
  • alkylene radicals include, but are not limited to, methylene, ethylene (CH 2 CH 2 ), propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.
  • cycloalkyl denotes a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • C 3-7 cycloalkyl refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.
  • haloalkyl denotes a unbranched or branched chain alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by a halogen.
  • Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl.
  • haloalkoxy refers to a group —OR where R is haloalkyl as defined herein.
  • haloalkylthio refers to a group —SR where R is haloalkyl as defined herein.
  • alkoxy as used herein means an —O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including their isomers.
  • “Lower alkoxy” as used herein denotes an alkoxy group with a “lower alkyl” group as previously defined.
  • C 1-10 alkoxy refers to an —O-alkyl wherein alkyl is C 1-10 .
  • acyl denotes a group of formula —C( ⁇ O)R wherein R is hydrogen or lower alkyl as defined herein.
  • alkylcarbonyl denotes a group of formula C( ⁇ O)R wherein R is alkyl as defined herein.
  • C 1-6 acyl refers to a group —C( ⁇ O)R contain 6 carbon atoms.
  • arylcarbonyl as used herein means a group of formula C( ⁇ O)R wherein R is an aryl group; the term “benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.
  • aryl denotes a monovalent aromatic carbocyclic radical containing 5 to 15 carbon atoms consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with one or more, preferably one or three substituents independently selected from hydroxy, thio, cyano, alkyl, alkoxy, lower haloalkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl, alkyl
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 3,4-methylenedioxyphenyl, 1,2,3,4-tetrahydroquinolin-7-yl, and the like.
  • the point of attachment of bicyclic aryl substituents with a heteroatom in one of the rings is on the carbocyclic aromatic ring.
  • heteroaryl or “heteroaromatic” as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character.
  • heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazole, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbony
  • bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, 3 benzothiazole and benzisothiazole.
  • Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.
  • the term “(hetero)aryl” or “(het)aryl” is used to indicate that a particular moiety can be either an aryl or a heteroaryl group.
  • heteroarylalkyl or “heteroaralkyl” means the radical of the formula R′R′′, wherein R′ is an optionally substituted heteroaryl radical as defined herein, and R′′ is an alkylene radical as defined herein with the understanding that the attachment point of the heteroaryl radical will be on the alkylene radical.
  • heteroarylalky radicals include, but are not limited to, 2-imidazolylmethyl, and 3-pyrrolylethyl.
  • alkoxycarbonyl and “aryloxycarbonyl” as used herein denotes a group of formula —C( ⁇ O)OR wherein R is alkyl or aryl respectively and alkyl and aryl are as defined herein.
  • amino refers to —NH 2 , —NHR and —NR 2 respectively and R is alkyl as defined above.
  • R is alkyl as defined above.
  • the two alkyl groups attached to a nitrogen in a dialkyl moiety can be the same or different.
  • aminoalkyl refers to NH 2 (CH 2 ) n —, RHN(CH 2 ) n —, and R 2 N(CH 2 ) n — respectively wherein n is 1 to 6 and R is alkyl as defined above.
  • C 1-10 alkylamino refers to an-aminoalkyl wherein alkyl is C 1-10 .
  • phenylamino refers to —NHPh wherein Ph represents an optionally substituted phenyl group.
  • acylamino denotes a group of formula —NHC( ⁇ O)R wherein R is hydrogen or lower alkyl as defined herein.
  • C 1-6 acyl-amino refers to an acylamino group wherein the C( ⁇ O)R moiety contains a total of 6 carbon atoms.
  • halogen or “halo” as used herein means fluorine, chlorine, bromine, or iodine.
  • cyanoalkyl refers to a group RR 1 wherein R is cyano and R 1 is an alkylene group as defined herein.
  • heteroalkyl as used herein means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of —OR a , —NR b R c , and —S(O) n R d (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein R a is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R b and R c are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R d is hydrogen, alkyl, cycloalkyl, or cycl
  • Representative examples include, but are not limited to, 2-hydroxy-ethyl, 3-hydroxy-propyl, 2-hydroxy-1-hydroxy-methylethyl, 2,3-dihydroxy-propyl, 1-hydroxy-methylethyl, 3-hydroxy-butyl, 2,3-dihydroxy-butyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-amino-propyl, 2-methylsulfonyl-ethyl, aminosulfonyl-methyl, aminosulfonyl-ethyl, aminosulfonyl-propyl, methylaminosulfonyl-methyl, methylaminosulfonyl-ethyl, methylaminosulfonyl-propyl, and the like.
  • azetidine refers to a 4-, 5-, 6- or 7-membered cycloalkane respectively wherein a nitrogen atom replaces one carbon atom.
  • N-oxides are well known and may be carried out, for example, in suitable organic solvent (dichloromethane, chloroform, benzene, hexane or t-butanol, etc.) in the presence of an excess of oxidizing agent (e.g., sodium peroxide, hydrogen peroxide, sodium periodate, sodium perborate, meta-chloroperbenzoic acid or other peracid, OXONE® (potassium peroxymonosulfate), potassium permanganate or chromic acid) typically at temperatures from 20-60° C.
  • suitable organic solvent e.g., dichloromethane, chloroform, benzene, hexane or t-butanol, etc.
  • oxidizing agent e.g., sodium peroxide, hydrogen peroxide, sodium periodate, sodium perborate, meta-chloroperbenzoic acid or other peracid, OXONE® (potassium peroxymonosulfate), potassium permangan
  • heteroaryl R 1 groups designated as pyridinyl, pyrimidinyl, thiophenyl, pyrrolyl, thiazolinyl, imidazolinyl or quinolyl can be linked to the pyrimidine at any carbon at on the heteroaryl ring.
  • wild type refers to the HIV virus strain which possesses the dominant genotype which naturally occurs in the normal population which has not been exposed to reverse transcriptase inhibitors.
  • wild type reverse transcriptase used herein has refers to the reverse transcriptase expressed by the wild type strain which has been sequenced and deposited in the SwissProt database with an accession number P03366.
  • reduced susceptibility refers to about a 10 fold, or greater, change in sensitivity of a particular viral isolate compared to the sensitivity exhibited by the wild type virus in the same experimental system
  • NRTI nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTI nucleoside and nucleotide reverse transcriptase inhibitors
  • Typical suitable NRTIs include zidovudine (AZT; RETROVIR®) from GSK; didanosine (ddI; VIDEX®) from Bristol-Myers Squibb Co. (BMS); zalcitabine (ddC; HIVID®) from Roche; stavudine (d4T; ZERIT®) from BMS; lamivudine (3TC; EPIVIR®) from GSK; abacavir (1592U89; ZIAGEN®) disclosed in WO96/30025 and available from GSK; adefovir dipivoxil (bis(POM)-PMEA; PREVON®) Gilead Sciences; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by BMS; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under
  • nevirapine BI-RG-587; VIRAMUNE®
  • BI Boehringer Ingelheim
  • delaviradine BHAP, U-90152
  • RESCRIPTOR® delaviradine
  • efavirenz DMP-266, SUSTIVA®
  • NNRTIs currently under investigation include PNU-142721, a furopyridine-thio-pyrimide under development by Pfizer; capravirine (S-1153 or AG-1549; 5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbonate) by Shionogi and Pfizer; emivirine [MKC-442; (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione)] by Mitsubishi Chemical Co.
  • protease inhibitor means inhibitors of the HIV-1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-1.
  • HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN® as well as nonpeptide protease inhibitors e.g., VIRACEPT®.
  • Typical suitable PIs include saquinavir available in hard gel capsules as INVIRASE® and in soft gel capsules as FORTOVASE® from Roche; ritonavir (ABT-538) available as NORVIR from Abbott Laboratories; Lopinavir (ABT-378) also available from Abbot; KALETRA®, is co-formulation lopinavir and a sub-therapeutic dose of ritonavir available from Abbott Laboratories; indinavir (MK-639) available as CRIXIVAN® from Merck & Co.; nelfnavir (AG-1343) available as VIRACEPT® from Agouron Pharmaceuticals, Inc.; amprenavir (141W94) available as AGENERASE® from Vertex Pharmaceuticals, Inc.
  • tipranavir PNU-140690
  • APTIVUS® tipranavir
  • lasinavir BMS-234475/CGP-61755
  • BMS lasinavir
  • BMS-2322623 an azapeptide under development by BMS as a 2nd-generation HIV-1 PI
  • GW-640385X VX-385
  • AG-001859 in preclinical development by Agouron/Pfizer
  • SM-309515 under development by Sumitomo Pharmaceuticals.
  • Additional PIs in preclinical development include N-cycloalkylglycines by BMS, ⁇ -hydroxyarylbutanamides by Enanta Pharmaceuticals; ⁇ -hydroxy- ⁇ -[[(carbocyclic- or heterocyclic-substituted)amino)carbonyl]alkanamide derivatives; ⁇ -hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides by Merck; dihydropyrone derivatives and ⁇ - and ⁇ -amino acid hydroxyethylamino sulfonamides by Pfizer; and N-aminoacid substituted L-lysine derivatives by Procyon.
  • WO0039125 (D. R. Armour et al.) and WO0190106 (M. Perros et al.) disclose heterocyclic compounds that are potent and selective CCR5 antagonists.
  • Miraviroc (UK-427,857; MVC) has advanced by Pfizer to phase III clinical trials and show activity against HIV-1 isolates and laboratory strains (P. Dorr et al., Antimicrob. Agents Chemother. 2005 49(11):4721-4732; A. Wood and D. Armour, Prog. Med. Chem. 2005 43:239-271; C. Watson et al., Mol. Pharm. 2005 67(4):1268-1282; M. J. Macartney et al., 43 rd Intersci.
  • GSK-873140 (ONO-4128, E-913, AK-602) was identified in a program initiated at Kumamoto University (K. Maeda et al. J. Biol. Chem. 2001 276:35194-35200; H. Nakata et al. J. Virol. 2005 79(4):2087-2096) and has been advanced to clinical trials.
  • Astra Zeneca disclose 4-amino piperidine compounds which are CCR5 antagonists.
  • TNX-355 is a humanized IgG4 monoclonal antibody that binds to a conformational epitope on domain 2 of CD4. (L. C. Burkly et al., J. Immunol. 1992 149:1779-87) TNX-355 can inhibit viral attachment of CCR5-, CXCR4- and dual/mixed tropic HIV-1 strains. (E.
  • Macromolecular therapeutics including antibodies, soluble receptors and biologically active fragments thereof have become an increasingly important adjunct to conventional low molecular weight drugs.
  • Antibodies with high specificity and affinity can be targeted at extra-cellular proteins essential for viral cell fusion.
  • CD4, CCR5 and CXCR4 have been targets for antibodies which inhibit viral fusion.
  • Olsen et al. J. Virol. 1999 73(5):4145-4155 disclose monoclonal antibodies capable of inhibiting (i) HIV-1 cell entry, (ii) HIV-1 envelope-mediated membrane fusion, (iii) gp120 binding to CCR5 and (iv) CC-chemokine activity.
  • Synergism between the anti-CCR5 antibody Pro140 and a low molecular weight CCR5 antagonists have been disclosed by Murga et al. (3rd IAS Conference on HIV Pathogenesis and Treatment, Abstract TuOa.02.06. Jul. 24-27, 2005, R10 de Janeiro, Brazil)
  • Anti-CCR5 antibodies have been isolated which inhibit HIV-1 cell entry also have been disclosed by M. Brandt et al. in U.S. Ser. No. 11/394,439 filed Mar. 31, 2006.
  • FUZEON® (T-20, DP-178, pentafuside) is disclosed in U.S. Pat. No. 5,464,933.
  • T-20 and an analog, T-1249, are analogs of HIV gp41 fragment which are effectively inhibit a conformational change required for HIV fusion.
  • T-20 has been approved and is available from Roche and Trimeris.
  • FUZEON is administered as a continuous sc infusion or injection in combination therapy with other classes of anti HIV drugs.
  • antiviral agents which may be useful in HIV therapy include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside.
  • Hydroyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI and is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine.
  • IL-2 is disclosed in Ajinomoto EP-0142268, Takeda EP-0176299, and Chiron U.S. Pat. Nos.
  • IL-12 is disclosed in WO96/25171 and is available from Roche and Wyeth Pharmaceuticals.
  • Ribavirin, 1- ⁇ -D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is described in U.S. Pat. No. 4,211,771 and is available from ICN Pharmaceuticals.
  • Abbreviations used in this application include: acetyl (Ac), acetic acid (HOAc), azo-bis-isobutyrylnitrile (AIBN), 1-N-hydroxybenzotriazole (HOBt), atmospheres (Atm), high pressure liquid chromatography (HPLC), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), methyl (Me), tert-butoxycarbonyl (Boc), acetonitrile (MeCN), di-tert-butyl pyrocarbonate or boc anhydride (BOC 2 O), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), benzyl (Bn), m-chloroperbenzoic acid (MCPBA), butyl (Bu), methanol (MeOH), benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyl diimidazole (
  • the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about ⁇ 78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20° C.
  • reaction of a phenol with 10a affords the ether 10b.
  • Subsequent displacement of the 2-chloro substituent with 12 affords 14a.
  • Deprotection by mild acid treatment afforded 14b which was alkylated on the piperidine nitrogen with an optionally substituted benzyl halide to afford the compounds of TABLE 1.
  • the compounds can be prepared from 2-methylthio-4-chloropyrimidine (26a, Route A2)
  • a base is, for example, an alkali metal or alkaline metal carbonate or hydroxide, such as Na 2 CO 3 , K 2 CO 3 , CaCO 3 , Cs 2 CO 3 , NaOH or KOH or an organic amine base such as, pyridine, 2,6-lutidine, collidine, TEA, NMM, DBU or DBN.
  • an alkali metal or alkaline metal carbonate or hydroxide such as Na 2 CO 3 , K 2 CO 3 , CaCO 3 , Cs 2 CO 3 , NaOH or KOH
  • an organic amine base such as, pyridine, 2,6-lutidine, collidine, TEA, NMM, DBU or DBN.
  • an alkali metal hydride such as NaH or KH
  • an alkali metal amide such as NaNH 2 , KNH 2 , LiN(SiMe 3 ) 2
  • the reaction is conveniently carried out in an inert solvent such as an ether solvent, e.g., THF, DME or dioxane, an aromatic hydrocarbon solvent, e.g., toluene, or a polar aprotic solvent such as DMF, NMP or DMSO.
  • the reaction is conveniently effected at a temperature in the range of 10-120° C. Subsequent displacement of the 2-chloro substituent was conveniently carried out in the presence of neat amine 12 at elevated temperatures.
  • the Boc protecting group is labile under acidic conditions and it can be removed by treatment with TFA or HCl in a solvent like DCM, dioxane or THF preferable at RT (see Protective Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd Edition, 1999, Wiley-Interscience).
  • Alkylation of piperidine nitrogen is accomplished by treating the amine or a metal salt of the amine (i.e. a deprotonated form) with an alkylating agent Ar 2 CH 2 Z 1 wherein Ar 2 is optionally substituted phenyl or optionally substituted heteroaryl moiety, Z 1 is a leaving group such as halo, mesylate, benzenesulphonyloxy or tosylate, optionally in the presence of a base and/or a phase transfer catalyst such as 18-crown-6 (SCHEME A, step 4a).
  • Ar 2 is optionally substituted phenyl or optionally substituted heteroaryl moiety
  • Z 1 is a leaving group such as halo, mesylate, benzenesulphonyloxy or tosylate, optionally in the presence of a base and/or a phase transfer catalyst such as 18-crown-6 (SCHEME A, step 4a).
  • the reaction may typically be carried out in the presence of a base such as TEA, DIPEA, DBU, or an inorganic base such as Na 2 CO 3 , NaHCO 3 , K 2 CO 3 or Cs 2 CO 3 , and in a solvent such as MeCN, DMF, DMSO, 1,4-dioxane, THF or toluene.
  • a base such as TEA, DIPEA, DBU, or an inorganic base such as Na 2 CO 3 , NaHCO 3 , K 2 CO 3 or Cs 2 CO 3
  • a solvent such as MeCN, DMF, DMSO, 1,4-dioxane, THF or toluene.
  • a metal salt of the amine i.e. a deprotonated form
  • THF 1,4-dioxane
  • Reductive amination is preferably carried out carried out by combining an amine and carbonyl compound in the presence of a complex metal hydride reducing agent such as NaBH 4 , LiBH 4 , NaB(CN)H 3 , Zn(BH 4 ) 2 , NaB(OAc) 3 H or borane/pyridine complex conveniently at a pH of 1-7, or with hydrogen in the presence of a hydrogenation catalyst, e.g. in the presence of Pd/C, at a hydrogen pressure of 1 to 5 bar, preferably at temperatures between 20° C.
  • a complex metal hydride reducing agent such as NaBH 4 , LiBH 4 , NaB(CN)H 3 , Zn(BH 4 ) 2 , NaB(OAc) 3 H or borane/pyridine complex conveniently at a pH of 1-7, or with hydrogen in the presence of a hydrogenation catalyst, e.g. in the presence of Pd/C, at a hydrogen pressure of 1 to 5 bar, preferably at temperatures between 20° C
  • a dehydrating agent such as molecular sieves or Ti(IV)(O-i-Pr) 4
  • a dehydrating agent such as molecular sieves or Ti(IV)(O-i-Pr) 4
  • N-aralkyl-4-amino-piperidine e.g., 4-amino-N-benzylpiperidine, CASRN 50541-93-0
  • N-heteroaralkyl-4-amino-piperidine is available or is prepared from a selectively protected precursor such as 4-(tert-butoxycarbonylamino)piperidine (CASRN 73874-95-0)
  • the fully elaborated piperidinyl side chain can be introduced in a single step (SCHEME A, step 4c).
  • Oxidation to the sulfone is readily accomplished with peroxy acids or with MoO 5 .HMPA.H 2 O (E. Vedejs et al., J. Org, Chem. 1978 43:188-196).
  • Introduction of the 1-tert-butoxycarbonyl-4-aminopiperidine (step 3) and subsequent bromination (step 4) of the pyrimidine ring with NBS affords 24a.
  • Deprotection (step 5) and alkylation of the piperidine nitrogen (step 6) is carried out as described above.
  • N 2 -(1-Benzyl-piperidin-4-yl)-N 4 -phenyl-pyrimidine-2,4-diamines are prepared from 4-chloro-2-methylthio-pyrimidine (CAS Reg No. 49844-90-8, J.-P. Roduit WO2000/063184) as depicted in SCHEME C.
  • the reaction sequence parallels that described in SCHEME A except methylthio moiety is used initially to suppress reactivity at the 2 position during the first amination (step 1) then to activate the 2-position after the electron donating aryl amine is introduced at the 4 position.
  • step 2 Oxidation of the sulfide (step 2), displacement of the 2 methylsulfonyl (step 3) with 1-tert-butoxycarbonyl-4-aminopiperidine, removal of the Boc group (step 4) and introduction of the optionally substituted benzyl moiety (step 5) is carried out as
  • the olefin can be substituted with electron-donating or electron-withdrawing groups.
  • a variety of palladium species can be utilized including, but not limited to Pd(OAc) 2 and Pd 2 (dba) 3 .
  • Phosphine ligands are incorporated into the reaction mixture to solubilize Pd(0) and a range of bases are also added including, but not limited to NaHCO 3 , K 2 CO 3 , Ag 2 CO 3 , Cs 2 CO 3 .
  • the reaction is typically run in aprotic solvents, however, a wide range of solvent polarities are compatible with the reaction.
  • the process is completed by removal of the Boc protecting group (step 2) and alkylation the piperidine nitrogen (step 3) as described previously.
  • Compounds of the present invention also can contain an optionally substituted 1-phenyl- or 1-heteroaryl-piperidin-4-ylamine substituent in place of the 1-benzyl-piperidin-4-ylamine (TABLES IV and V).
  • the aryl or heteroaryl substituent typically is introduced onto the piperidine ring prior to incorporation onto the pyrimidine core.
  • Fluorine substituents are generally significantly more labile than other halogen substituents. While hard nucleophiles like water and hydroxide fail to displace fluoride, soft nucleophiles like phenols, imidazoles, amines, thiols and some amides undergo facile displacement reactions even at room temperature (D. Boger et al., Biorg. Med. Chem. Lett. 2000 10:1471-75; F. Terrier Nucleophilic Aromatic Displacement: The Influence of the Nitro Group VCH Publishers, New York, N.Y. 1991). Removal of the protecting group (step 3) affords the requisite 1-phenyl-piperidin-4-ylamine 44b.
  • the 1-(hetero)aryl-piperidin-4-yl amine was introduced into the pyrimidine using reaction sequences analogous to those exemplified in SCHEMES A and C for the corresponding benzyl derivatives in TABLES IV and V.
  • the 4-aryloxy compounds were prepared from 10b or 4-arylamines were prepared from 28.
  • Incorporation of the acrylonitrile side chain was accomplished by treating 50a with acrylonitrile under Heck coupling conditions.
  • the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
  • Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups, or suspensions.
  • Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) parenteral, intramuscular, intravenous, and suppository administration, among other routes of administration.
  • the preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.
  • a compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
  • a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • excipient as used herein includes both one and more than one such excipient.
  • phrases “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic
  • the preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds of the present invention may be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the present invention may be formulated for nasal administration.
  • the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
  • the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
  • Compounds in transdermal delivery systems are frequently attached to a skin-adhesive solid support.
  • the compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza-cycloheptan-2-one).
  • Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection.
  • the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid.
  • Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
  • terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
  • the status of an HIV infection can be monitored by measuring viral load (RNA) or monitoring T-cell levels.
  • RNA viral load
  • T-cell levels The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
  • a daily dosage between about 0.01 and about 100 mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy.
  • a preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day. Thus, for administration to a 70 kg person, the dosage range would be about 7 mg to 0.7 g per day.
  • the daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached.
  • One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
  • the active compound or a salt can be administered in combination with another antiviral agent, such as a nucleoside reverse transcriptase inhibitor, another non-nucleoside reverse transcriptase inhibitor or HIV protease inhibitor.
  • another antiviral agent such as a nucleoside reverse transcriptase inhibitor, another non-nucleoside reverse transcriptase inhibitor or HIV protease inhibitor.
  • the active compound or its derivative or salt are administered in combination with another antiviral agent the activity may be increased over the parent compound.
  • the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives.
  • Concurrent administration as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.
  • references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions, and that the treatment of animals includes the treatment of humans as well as other animals.
  • treatment of a HIV infection also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HIV infection, or the clinical symptoms thereof.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • I-53 was prepared analogously except 56 was replaced with 3-chloro-5-methyl-4-[2-(piperidin-4-ylamino)-pyrimidin-4-yloxy]-benzonitrile and 59 was replaced 4-bromomethyl-3-chloro-benzamide.
  • I-51, I-59 and I-60 were prepared analogously except 56 was replaced with 4-[5-bromo-2-(piperidin-4-ylamino)-pyrimidin-4-yloxy]-3-chloro-5-methyl-benzonitrile and 59 was replaced with 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene, 4-bromomethyl-3-chloro-benzamide and 4-bromomethyl-3-chloro-benzenesulfonamide respectively.
  • step 1 NBS (100 mmol) was added to a mixture of 60a (100 mmol) in HOAc (200 mL) and the mixture was stirred at RT overnight. The HOAc was removed and the residue was diluted with EtOAc and washed with saturated Na 2 CO 3 . The combined organic phase was dried (Na 2 SO 4 ), filtered and evaporated to afford 60b as white solid that was used without further purification.
  • step 2 3-chloro-4-hydroxy-5-methyl-benzonitrile (60c) can be prepared from 60b as described by G. D. Diana and T. J. Nitz in U.S. Pat. No. 5,464,848.
  • step 3 To a solution of 60c (6.9 mmol) in NMP (10 mL) was added portion wise NaH (7.3 mmol) and the mixture was stirred at RT for 30 min. To the resulting solution was added 26a (7.3 mmol) and the reaction mixture was stirred at 140° C. in microwave for 3 h. The reaction mixture was cooled and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to afford 62a that was used in the next step without purification.
  • step 4 MCPBA (6 mmol) was added portion wise to a solution of 62a (6.9 mmol) in DCM (30 mL) cooled to 0° C. After the reaction mixture was warmed to RT and stirred for 3 h. The reaction mixture was quenched with NaHSO 3 , diluted with DCM and washed with saturated Na 2 CO 3 , water and brine. The organic phase was dried (Na 2 SO 4 ) and the solvent was evaporated. The residue was purified by SiO 2 column chromatography eluting with EtOAc/hexane (2:1) to afford intermediate 1.8 g (83% for 2 steps) of 62b.
  • step 5 A mixture of 62b (3.8 mmol) and 12 (4.2 mmol) in NMP (10 mL) was stirred at 120° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC eluting with MeCN/H 2 O to afford 0.600 g (36%) of 64a as white solid.
  • step 6 Trifluoroacetic acid (0.5 mL) was added to a solution of 64a (0.47 mmol) in DCM (10 mL) at RT. The mixture was stirred at RT overnight. The solvent was removed to afford 0.400 g (100%) of 64b that was used without further purification.
  • step 7 A mixture of 64b (0.175 mmol), 66 (0.175 mmol, CASRN 180200-86-6) and TEA (0.2 mL) in NMP (1 mL) was stirred at RT for 2 h.
  • the reaction mixture was purified by preparative HPLC eluting with MeCN/H 2 O to afford 0.078 g (82%) of I-48 as white solid.
  • I-26 was prepared analogously except in step 3, 60c was replaced by 3,5-dimethyl-4-hydroxy-benzonitrile (CASRN 4198-90-7) and in step 7,1-bromomethyl-2-chloro-4-methanesulfonyl-benzene was replaced with 4-bromomethyl-3-chlorobenzamide (prepared by NBS bromination of 3-chloro-4-methyl-benzamide, CASRN 24377-95-5).
  • I-27 was prepared analogously except in step 3, 60c was replaced with 3,5-dimethyl-4-hydroxy-benzonitrile (70, CASRN 4198-90-7).
  • I-29 was prepared analogously except in step 3, 60c was replaced by 70 and in step 7,1-bromomethyl-2-chloro-4-methanesulfonyl-benzene was replaced with 4-bromomethyl-3-chloro-benzonitrile.
  • step 1 sodium hydride (1 mmol, 60% in oil) was added in portion to a solution of 70 in THF at RT. The resulting solution was stirred for 10 min, then 2,4-dichloropyrimidine (1 mmol, CAS Reg No. 3934-20-1) was added. The reaction mixture was stirred for 6 h at RT. After the reaction was complete the solvent was removed in vacuo to afford 0.230 g (88.8%) of 68b which was used directly in next step.
  • step 2 A mixture of 68b (1 mmol) and 12 (1 mmol) was fused at 150° C. for 2 h. The reaction mixture was cooled and purified by SiO 2 chromatography eluting with EtOAc/hexane (1:2) to afford 0.210 g (49.6%) of 72a.
  • step 3 To a solution of 72a (1 mmol) in DCM was added TFA (1 mL), the resulting solution was stirred at RT for 5 h. After the reaction was complete the solvents were removed in vacuo to afford 0.460 g (100%) of the TFA salt of 72b as a yellow oil which was used in the next step without purification.
  • step 4 To a solution of 72b (0.2 mmol) in MeCN was added TEA (0.3 mmol) and 73 (0.2 mmol) and the resulting mixture was stirred at RT for 6 h. After the reaction was complete, the solvent was evaporated and the residue purified by preparative HPLC on a 30 ⁇ 100 mm C18 ORB column eluting with MeCN/H 2 O to afford 0.023 g (22%) of I-23.
  • the title compound was prepared by NBS/AIBN mediated bromination of 3-chloro-4-methyl-benzenesulfonamide (CASRN 51893-27-6, R. Wigwag et al., U.S. Publication No. 20050282793).
  • step 1 sodium hydride (1 mmol, 60% in oil) was added in portion to a solution of 74 (1 mmol) in NMP at RT. The resulting solution was stirred for 5 min, and then 26a (1 mmol) was added. The reaction mixture was stirred for 30 min at 150° C. in a microwave. After the reaction was complete, EtOAc and H 2 O were added and the aqueous phase was extracted with EtOAc. The organic extracts were dried (Na 2 SO 4 ), filtered and the solvent was evaporated to afford 0.234 g (84.4%) of 76a which was used in the next step without purification.
  • step 2 To a solution of 76a (1 mmol) in DCM was added MCPBA (4 mmol) and the resulting mixture was stirred at RT for 4 h. After the reaction was complete, the reaction mixture was washed sequentially with saturated NaHSO 3 and saturated NaHCO 3 solution. The organic phase was dried (Na 2 SO 4 ) and concentrated in vacuo to afford 0.304 g (98%) of 76b.
  • step 3 To a solution of 76b (1 mmol) in NMP was added 12 (1 mmol) and the resulting mixture was stirred at 150° C. for 30 min. After the reaction was complete, the resulting mixture of 78 and the by-produce from displacement at the 4-position 79 was purified by SiO 2 column chromatography eluting with EtOAc/hexane (1:2) to afford 0.107 g (24.5%) of 78.
  • step 4 To a solution of 78 (0.2 mmol) in DCM was added TFA (1 mL) and the resulting solution was stirred at RT for 5 h. After the reaction was completed, the solvents were concentrated in vacuo to afford 0.098 g (100%) of a yellow oil which was directly used the next step without purification.
  • step 5 To a solution of secondary amine from step 4 (0.1 mmol) in MeCN was added Et 3 N (0.3 mmol) and 73 and the reaction was stirred at RT for 3 h. The solvent was evaporated and the residue was purified by preparative HPLC by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.006 g (11%) of I-25.
  • 3-Amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 80 was prepared by the procedure of D. Marquess et al. disclosed in WO2005/080389.
  • step 1 A mixture of 70 (10 mmol), 68a (10 mmol) and K 2 CO 3 (15 mmol) in DMF (20 mL) was stirred at RT for 6 h. The mixture was poured into water (50 mL) and extracted with EtOAc. The organic phase was washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. The residue containing 68b was used in the next step without purification.
  • step 2 A mixture of 68b (2 mmol) and 80 (2 mmol) in n-BuOH was heated in a sealed tube at 160° C. for 6 h. When no starting material was detected by TLC, the reaction was cooled to RT and concentrated in vacuo. The crude product 82a was used in the next step without further purification.
  • step 3 TFA (2 mL) was added to a solution of 82a (1 mmol) in DCM (10 mL) at RT. The mixture was stirred at RT overnight and the solvent was evaporated to afford 0.349 g (100%) of 82b.
  • step 4 A mixture of 82b (1 mmol), 84 (1 mmol) and TEA (0.1 mL) in MeCN (2 mL) was stirred at RT overnight.
  • the reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.0424 g (82%) of I-46.
  • I-47 was prepared analogously except in step 4,4-bromomethyl-3-chlorobenzamide was replaced with 4-bromomethyl-3-chloro-benzenesulfonamide.
  • I-49, I-50 and I-56 were prepared analogously except in step 1, 68a was replaced with 5-bromo-2,4-dichloro-pyrimidine and, in the preparation of I-49 and I-56, in step 4, 4-bromomethyl-3-chlorobenzamide was replaced with 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene and benzyl bromide respectively.
  • step 1 A mixture of 84 (20 mg, 0.922 mmol, CASRN 3932-97-6), 70 (176 mg, 1.2 mmol), K 2 CO 3 (1.27 g, 9.22 mmol) in DMF (20 mL) was stirred at RT overnight. The reaction mixture was poured into H 2 O (20 mL) and extracted with EtOAc (3 ⁇ 10 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford 0.2387 g (79%) of 86.
  • step 2 A mixture of the 86 (200 mg, 0.61 mmol) and 12 (147 mg, 0.73 mmol) was heated to 150° C. overnight.
  • the reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.182 g (61%) of 88a as white solid.
  • step 3 TFA (2 mL) was added to a solution of 88a (0.1 mmol) in DCM (10 mL) at RT and stirred overnight. The solvent was removed to afford 0.0392 g (100%) of 88b which was used without additional purification.
  • step 4 A mixture of 88b (0.1 mmol), 66 (0.1 mmol) and TEA (0.1 mL) in MeCN (2 mL) was stirred at RT overnight.
  • the reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.0487 g (82%) of I-55.
  • step 1 A mixture of 90 (500 mg, 2.99 mmol, CASRN 2927-71-1), 70 (485 mg, 3.3 mmol) and K 2 CO 3 (1.24 g, 9 mmol) in DMF (20 mL) was stirred at RT overnight. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 ⁇ 10 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford 0.633 g (76%) of 92.
  • step 2 A mixture of 92 (630 mg, 2.27 mmol) and 12 (460 mg, 2.3 mmol) was heated to 150° C. overnight at which time no starting material was detected by TLC.
  • the reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.610 g (61%) of 94a as white solid.
  • step 3 TFA (2 mL) was added to a solution of 94a (1 mmol) in DCM (10 mL) at RT. The mixture was stirred at RT overnight and the solvent was removed in vacuo to afford 0.341 g (100%) of 94b which was used without additional purification.
  • step 4 A mixture of 94b (0.1 mmol), 66 (0.1 mmol) and TEA (0.1 mL) in MeCN (2 mL) was stirred at RT overnight.
  • the reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.035 g (72%) of I-57.
  • step 1 sodium hydride (1 mmol, 60% in oil) was added portion wise to a solution of 70 in NMP at RT and the resulting solution was stirred for 10 min. To the sodium phenoxide solution was added 96 (1 mmol) and the resulting mixture was stirred for 30 h at 150° C. After the reaction was complete, the reaction was partitioned between EtOAc and H 2 O and the water phase was extracted with EtOAc. The combined extracts were dried (Na 2 SO 4 ), filtered and the solvent was evaporated to afford 98a as an oil which was used in the next step without further purification.
  • step 2 To a solution of 98a in DCM was added MCPBA (4 mmol) and the resulting mixture was stirred at RT for 4 h. After the reaction was complete, the reaction mixture was washed sequentially with saturated NaHSO 3 and saturated NaHCO 3 . The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford 0.123 g (38.6%) of 98b which was used without further purification.
  • step 3 A mixture of intermediate 98b (0.5 mmol) and 12 (0.5 mmol) was fused and heated at 150° C. for 2 h to afford 0.197 g (90%) of 100 which was used directly in the next step without purification.
  • step 4 To a solution of 100 (0.5 mmol) in DCM was added portion wise NBS (0.5 mmol). The resulting mixture was stirred for 10 min at RT. The reaction was quenched with water, the mixture was extracted with DCM, dried (Na 2 SO 4 ), filtered and the solvent was removed in vacuo afford 0.273 g (100%) of 102a as a yellow oil which was directly used in the next step without purification.
  • step 5 To a solution of 102a (0.5 mmol) in DCM was added TFA (2.5 mL) and the resulting solution was stirred at RT for 5 h. After the reaction was complete, the solvents were concentrated in vacuo to afford 0.273 g (100%) of 102b as a yellow oil which was used the next step without purification.
  • step 6 To a solution of 102b (0.2 mmol) in MeCN was added TEA (0.4 mmol) and 84 (0.2 mmol), the resulting mixture was stirred at RT for 6 h. After the reaction was complete, the solvent was evaporated. The residue was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.021 g (18.8%) of II-2.
  • step 1 To a solution of 26a (1 mmol) in IPA was added 4-methyl-4-amino-benzonitrile (104, 1 mmol) then concentrated HCl (5 drops). The solution was stirred at 100° C. overnight. The reaction mixture was cooled and the resulting precipitate was filtered and washed thoroughly with IPA to afford 0.204 g (80%) of 106a.
  • step 2 To a solution of 106a (1 mmol) in DCM was added MCPBA (4 mmol) and the resulting mixture was stirred at RT for 4 h. After the reaction was complete, the reaction mixture was washed sequentially with saturated NaHSO 3 and saturated NaHCO 3 solution. The organic phase was dried (Na 2 SO 4 ), filtered and evaporated to afford 0.296 g (100%) of 106b.
  • step 3 To a solution of 106b (1 mmol) in NMP was added 12 (1 mmol) and the resulting mixture was stirred at 150° C. for 30 min. After the reaction was complete, the resulting mixture was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:2) to afford 0.080 g (20.8%) of 108.
  • III-2 (4-cyano-2,6-dimethyl-aniline, 73), III-4 (4-bromo-2,6-dimethyl-aniline, 73), III-6 (4-cyano-2,6-dimethyl-aniline, 84), III-8 (4-bromo-2,6-dimethyl-aniline, 66) and III-13 (4-cyano-2,6-dimethyl-aniline, iso-propyl 4-bromomethyl-3-chloro-benzoate).
  • III-14 was prepared by hydrolysis of III-13 with LiOH in aqueous THF.
  • step 2 2-Chloro-4-methylsulfonylbenzoic acid (65a, 21.3 mmol, CASRN 53250-83-2) was added under N 2 to a suspension of LiAlH 4 (25.5 mmol) in anhydrous THF (50 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred overnight. Water (1 mL), NaOH 15% (1 mL) and water (3 mL) were added sequentially to quench the reaction. The precipitate was filtered and the filtrate was extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and evaporated to afford 2-chloro-4-methylsulfonylbenzyl alcohol (65b) as colorless oil which was used in next step without further purification.
  • step 3 PBr 3 (40 mmol) was added to a solution of 65b (21.3 mmol) in Et 2 O (50 mL) and the reaction mixture was stirred at RT for 4 h. Water (1 mL) was added to quench the reaction. The mixture was diluted with Et 2 O and washed with water and brine. The organic phase was dried (Na 2 SO 4 ) and the solvent was evaporated. The residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:4) to afford 5.25 g (87%) of 2-chloro-4-methylsulfonylbenzyl bromide (66) as white solid.
  • step 4 A mixture of 26a (2 mmol) and 107 (2 mmol) was heated in neat in a sealed tube at 160° C. The reaction mixture became a clear solution after 30 min and started to solidify as the product formed. After 6 h, TLC indicated that no starting material remained. The crude product containing 109a was used in next step without further purification.
  • step 5 MCPBA (6 mmol) was added portionwise to a solution of compound 109a (2 mmol) in DCM (15 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 3 h. The reaction mixture was quenched with NaHSO 3 , diluted with DCM and washed sequentially with saturated Na 2 CO 3 , water, and brine. The organic phase was dried (Na 2 SO 4 ) and the solvent was evaporated. The residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:1) to afford 0.573 g (95%) of 109b.
  • step 6 A mixture of 109b (1.9 mmol) and 12 (2.1 mmol) in NMP (5 mL) was stirred at 150° C. overnight. Reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to give 0.422 g (63%) of 111a as white solid.
  • step 7 TFA (1 mL) was added to a solution of 111a (1 mmol) in DCM (10 mL) at RT. The mixture was stirred at RT overnight and the solvent was removed to afford 0.700 g (100%) of 111b.
  • step 8 A mixture of 111b (1 mmol), 66 (1 mmol) and TEA (0.1 mL) in NMP (2 mL) was stirred at RT overnight.
  • the reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.060 g (80%) of III-1 as white solid.
  • step 9 NBS (0.067 mmol) was added to a mixture of III-1 (0.067 mmol) in DCM (5 mL). The mixture was stirred at RT for 1 h and quenched with water (1 mL). The solvent was removed and the residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:2) to afford 0.030 g (64%) of III-5 as white solid.
  • III-7 (4-cyano-2,6-dimethyl-aniline, 4-bromomethyl-3-chloro-benzeneamide
  • III-11 (4-cyano-2,6-dimethyl-aniline, 4-bromomethyl-3-chloro-pyridine)
  • III-15 (2-chloro-4-cyano-6-methyl-aniline, 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene).
  • III-17 was prepared analogously except in step 8, 66 was replaced with iso-propyl 4-bromomethyl-3-chloro-benzoate and after step 9 the carboxylic acid ester was hydrolyzed with LiOH in aqueous THF.
  • step 1 A mixture of compound 109b (1.9 mmol) and 80 (2 mmol) in NMP (5 mL) was stirred at 150° C. overnight.
  • the crude reaction mixture was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.502 g (56%) of 120a as white solid.
  • step 2 TFA (2 mL) was added to a solution of compound 120a (1 mmol) in DCM (10 mL) at RT and stirred overnight. The volatile material was removed in vacuo to afford 0.709 g (100%) of 120b which was used without additional purification.
  • step 3 A mixture of 120b (0.1 mmol), 66 (0.1 mmol) and TEA (0.1 mL) in MeCN (2 mL) was stirred at RT overnight. The solvent was evaporated and the product purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.042 g (76%) of III-12
  • the starting material was prepared analogously to 108 (Example 13) except 4-bromo-2,6-dimethyl-aniline was used in place of 4-cyano-2,6-dimethyl-aniline in step 4.
  • step 1 A mixture of 112 (4.18 mmol), Pd(0)(OAc) 2 (0.836 mmol), tri-o-tolylphosphine (4.18 mmol), acrylonitrile (16.7 mmol) and TEA (16.7 mmol) in MeCN (20 mL) was stirred at 140° C. in a sealed tube for 48 h. The mixture was cooled, filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:3) to afford 0.560 g (30%) of 114a as white solid.
  • step 2 TFA (1 mL) was added to a solution of 114a (1.25 mmol) in DCM (10 mL) at RT. The mixture was stirred at RT overnight. The solvent was removed to afford 0.920 g (100%) of 114b.
  • step 3 A mixture of 114b (0.2 mmol), 66 (0.2 mmol) and TEA (1 mL) in NMP (2 mL) was stirred at RT for 2 h.
  • the reaction mixture was concentrated and purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.080 g (72%) of III-9 as white solid.
  • III-10 was prepared analogously except in step 3, 66 was replaced with 4-bromomethyl-3-chloro-benzamide (84).
  • 1H-16 was prepared by treating 111-9 with NBS as described in step 9 of Example 13.
  • step 1 (Method A)—A mixture of 3-fluorobenzonitrile (24.8 mmol), 116 (37.2 mmol, CASRN 73870-95-0) and K 2 CO 3 (49.6 mmol) in DMSO (21 mL) was stirred at 140° C. overnight. The cooled mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:3) to afford 6.5 g (87%) of 118a.
  • step 2 TFA (5 mL) was added to a mixture of 118a (21.5 mmol) in DCM (100 mL). The mixture was stirred at RT overnight then evaporated to afford 12 g (100%) of 118b which was used without further purification.
  • step 3 The mixture of compound 118b (0.5 mmol), 98b (0.6 mmol) and TEA (1 mmol) in NMP (2 mL) was stirred at 150° C. overnight. It was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.100 g (48%) of IV-4.
  • IV-5 and IV-6 was prepared analogously except in step 3, 98b was replaced with 4-(5-bromo-2-chloro-pyrimidin-4-yloxy)-2,6-dimethyl-benzonitrile (52) and 4-(2-chloro-pyrimidin-4-yloxy)-2,6-dimethyl-benzonitrile (68b), respectively.
  • IV-7 and IV-8 were prepared analogously utilizing 68b and 52 in place of 98b respectively and condensing each pyrimidine with 124 (see Example 18).
  • step 1 A mixture of 1-fluoro-3-methanesulfonyl-benzene (5 mmol) and 116 (5 mmol) in DIPEA (1 mL) and DMSO (10 mL) was heated at reflux for 48 h. After cooling, the mixture was poured into water (50 mL) and extracted with EtOAc. The organic phase was (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:2) to afford 0.970 g (77%) of 120a as white solid.
  • step 2 TFA (1 mL) was added to a solution of 120a (3.85 mmol) in DCM (10 mL) at RT. and stirred at RT overnight. The solvent was removed to afford 2.3 g (100%) of 120b which was used in the next step without further purification.
  • step 3 A mixture of 68b (0.0774 mmol), 120b (0.156 mmol) and DIPEA (0.2 ⁇ L) was heated at 130° C. in a sealed tube for 5 h. After cooling, the mixture was concentrated and purified by SiO 2 chromatography eluting with EtOAc/hexane (1:2) to afford 0.033 g (89%) of IV-10 as white solid.
  • IV-18 was prepared analogously using 68a and 1-(3-nitro-phenyl)-piperidin-4-ylamine (CAS Reg No. 461720-07-0 for TFA salt, U.S. Pub. No. 20040106622).
  • IV-31 is prepared by reduction of IV-18. Numerous methods for reduction of a nitro group to a primary amine exist and are well known within the art.
  • step 1 To a mixture of 118a (8.71 mmol) and NaOH (8.71 mmol) in EtOH (10 mL) was added H 2 O 2 (10 mL) dropwise at RT. The mixture was stirred at 50° C. for 0.5 h. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (2:1) to afford 2.51 g (90%) of 122.
  • step 2 TFA (5 mL) was added to a solution of 122 (8.3 mmol) in DCM (100 mL). The solution was stirred at RT overnight then evaporated in vacuo to afford 124 which was used in the next step without further purification.
  • step 3 To a solution of 109b (0.2 mmol) in NMP was added the TFA salt of 124 (0.2 mmol) and TEA (0.4 mmol). The reaction was stirred at 150° C. overnight, cooled and the solvent removed in vacuo. The residue was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.023 g (26%) of V-4.
  • V-1 (109b, 118a)
  • V-6 4-(4-bromo-2,6-dimethyl-phenoxy)-2-methanesulfonyl-pyrimidine, 120b)
  • V-12 (109a, 134a).
  • V-9 was prepared analogously except in step 3 109b was replaced with 3-chloro-4-(2-methanesulfonyl-pyrimidin-4-yloxy)-5-methyl-benzonitrile.
  • the latter is prepared by the condensation of 26a and 3-chloro-4-hydroxy-5-methyl-benzonitrile followed by MCPBA oxidation.
  • V-2 was prepared by condensation of 109b and 118a (from Example 20) as described in step 3 of the present example followed by NBS mediated bromination as described in step 9 of Example 13.
  • V-13 was prepared by condensation of 109b and 134b (from Example 20) as described in step 3 of the present example.
  • V-14 was prepared by condensation of 4-(5-bromo-2-methanesulfonyl-pyrimidin-4-ylamino)-3,5-dimethyl-benzonitrile, which was prepared by NBS mediated bromination of 109b, and 134b (see example 20) as described in step 3 of the present example.
  • V-5 and V-3 were prepared by NBS mediated bromination of V-1 and V-4, respectively, as described in step 9 of Example 13.
  • step 1 A mixture of 126 (4 mmol) and 124 (4.3 mmol) in NMP (8 mL) was stirred at 150° C. overnight. The solvent was evaporated and the crude product was purified by preparative HPLC on a 30 ⁇ 100 mm C18 ODB column eluting with MeCN/H 2 O to afford 0.475 g (24%) of 128 as white solid.
  • step 2 A mixture of 128 (0.12 mmol), Pd(0)(OAc) 2 (0.024 mmol), tri-o-tolylphosphine (0.12 mmol) and acrylonitrile (0.5 mL) in TEA (0.5 mL) and MeCN (5 mL) was stirred at 140° C. in a sealed tube for 48 h. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was purified by SiO 2 chromatography eluting with EtOAc to afford 0.0215 g (38%) of V-7 as a white solid.
  • V-8 was prepared analogously except (4-bromo-2-chloro-6-methyl-phenyl)-(2-methanesulfonyl-pyrimidin-4-yl)-amine (prepared from 4-bromo-2-chloro-6-methyl-phenylamine, CAS Reg. No 30273-42-8 and 26a as described in steps 4 and 5 of example 13) was used in step 1 in place of 126.
  • the tert-butoxycarbonyl protecting group was removed from the coupled product with TFA and DCM as described in step 2 of Example 17.
  • 3-(4-Amino-piperidin-1-yl)-5-chloro-benzamide (135a), 4-(4-amino-piperidin-1-yl)-benzamide (135b) and 2-(4-amino-piperidin-1-yl)-benzamide (135c) were prepared from 134k, 134n, 134o, respectively, using the procedure described in step 1 of example 18.
  • step 1 5-iodo-nicotinic acid (136a, CASRN 15366-65-1) is dissolved in MeOH and SOCl 2 (3 equivalents) is added and the reaction is heated at reflux for 4 h. The reaction mixture is cooled and the volatile solvents evaporated. The residue is partitioned between DCM and saturated NaHCO 3 and the DCM is dried (Na 2 SO 4 ), filtered and evaporated to afford 136b.
  • step 2 Cu(I) mediated condensation of 116 and 136b is carried our as using Method B as described in Example 20 to afford 138a.
  • steps 3 & 4 are carried out as described in steps 2 & 3 of example 18 to afford V-10.
  • V-11 was isolated as a byproduct of this reaction.
  • step 1 To a solution of 140 (1 mmol) in DCM (10 ml) was added EDC-HCl (1.1 mmol), HOBt (1.1 mmol), NMP (2.5 mmol). The resulting mixture was stirred at RT for 5 min, then 116 (1 mmol) was added and the reaction was stirred for 5 h. The mixture was quenched with a solution of 2% NaOH (10 mL) and extracted with DCM (3 ⁇ 10 mL). The combined organic extracts was washed with brine (15 mL), dried (Na 2 SO 4 ), filtered, and evaporated to afford 659 mg (97.4%) of 142 a white solid.
  • step 2 To a solution of 142 (1 mmol) in THF was added BH 3 -THF (1M, 4 mmol). The resulting mixture was stirred at 80° C. overnight. The reaction mixture was cooled to 0° C. and quenched by adding MeOH. After the solution was evaporated to dryness, the residue was purified by SiO 2 chromatography eluting with EtOAc/hexane (1:1) to afford 194 mg (60%) of 144a.
  • step 3 To a solution of 144a (0.3 mmol) in DCM was added TFA (1 mL) and the resulting solution was stirred at RT for 5 h. The solvents were concentrated in vacuo to afford a yellow oil (100%) which was used in the next step without further purification.
  • step 4 A solution of 68b (0.2 mmol) and 144b in DIPEA was heated to 120° C. in sealed tube for 5 h. The reaction mixture was purified by preparative HPLC to afford 29 mg (32%) of I-33 as white solid.
  • step 1 A mixture of 146a (100 mmol) and CuCN (200 mmol) in DMSO (50 mL) was stirred at 150° C. overnight. The mixture was poured into a mixture of water (200 mL) and EtOAc (200 mL). The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford product 146b (yield: 71.6%).
  • step 2 A mixture of 146b (10 mmol), 2,4-dichloro-5-bromo-pyrimidine (150, 10 mmol) and K 2 CO 3 (15 mmol) in DMF (20 mL) was stirred at RT for 6 h. The mixture was poured into water (50 mL) and extracted with EtOAc. The organic phase was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was used in the next step without further purification.
  • step 3 A mixture of 124 (0.0774 mmol), 148 (0.0774 mmol) and DIPEA (0.2 mL) was heated at 110° C. in a sealed tube for 5 h. After cooling, the mixture was concentrated and purified by SiO 2 chromatography to afford 0.037 g (89%) of IV-40 as white solid.
  • IV-32, IV-33, IV-34 and IV-35 were prepared using the same procedure except 124 was replaced with 3-(4-amino-piperidin-1-yl)-benzoic acid methyl ester which is prepared from methyl 3-bromobenzoate and 116 utilizing the conditions described in step 1 of example 27. Hydrolysis of the ester and conversion to the amide was carried out by EDCI catalyzed coupling of the resulting acid with methylamine, cyclopropylamine, 2-amino-ethanol and 2-dimethylamino-ethane-amine. A representative coupling procedure is described in step 5 of example 27.
  • step 1 Condensation of 70 and 152 (CASRN 1780-31-0) to afford 154 was carried out as described in step 2 of example 24.
  • step 2 A mixture of 124 (0.1 mmol), 154 (0.1 mmol) and DIPEA (0.2 mL) in DMSO (1 mL) was heated at 150° C. in a sealed tube overnight. After cooling, the mixture was concentrated and purified by SiO 2 chromatography to afford 0.033 g (73%) of IV-45.
  • step 1 To a solution of 156a (3.0 g, 21.5 mmol, CASRN 394-50-3) in MeOH (250 mL) was added Pd/C (300 mg) under an argon atmosphere. The mixture was heated at 50° C. for 3 d under a 50 psi hydrogen atmosphere. The catalyst was filtrated and the filtrate was concentrated in vacuo to afford 156b which was used in the next step without further purification.
  • step 2 To a solution of 156b (ca. 21.5 mmol from step 1) in HOAc (30 mL) in ice-water bath was added in portions NBS (4.0 g, 22.6 mmol). The mixture was warmed to RT and stirred overnight. Most of solvent was removed in vacuo. The residue was diluted with EtOAc then washed with water and brine. The organic phase was dried and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 2.8 g (63.7% for two steps) of 158a as a white solid.
  • step 3 To a solution of 158a (2.8 g, 13.7 mmol) in DMSO (16 mL) was added CuCN (3.68 g, 41 mmol). The mixture was heated at 140° C. under an Ar atmosphere overnight. The mixture was cooled to about 100° C. and poured slowly to stirred EtOAc. The mixture was filtrated. The filtrate was washed with H 2 O and the water phase was extracted with EtOAc. The combined organic extracts were washed with brine. The mixture was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography to afford to 1.72 g (80%) of 158b.
  • the phenol 158b was condensed with 150 as described in step 2 of example 24 to afford 160 which was condensed with 124 as described in step 3 of example 24 to afford II-48.
  • step 1 A mixture of (3-bromo-phenyl)-acetic acid methyl ester (162, 5 mmol), 116 (7 mmol), K 2 CO 3 (10 mmol), CuI (0.5 mmol) and L-proline (1 mmol) in DMSO (10 mL) was heated at 90° C. overnight. The cooled mixture was partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 0.91 g (74%) of 164a.
  • Step 2 was carried out as described in step 6 of example 5 to afford 164b.
  • Condensation of 164b and 166 (step 3) was carried out as described in step 3 of example 24 to afford 168a.
  • the requisite pyrimidine 166 was prepared by condensation of 3-chloro-4-hydroxy-5-methyl-benzonitrile and 152 as described in step 2 of example 24.
  • step 4 A mixture of 168a (1 mmol) and LiOH (10 mmol) in THF (3 mL) and H 2 O (1 mL) was heated to reflux and stirred overnight. TLC indicated that starting material was consumed. The solvent was removed and the mixture was diluted with water and pH adjusted to ca. 3 with 2 N HCl. The product was filtered and dried in vacuo to afford 458 mg (93%) of 168b (93%).
  • step 5 A mixture of 168b (0.1 ⁇ mol), EDCI (0.15 mmol) and HOBt (0.15 mmol) in DCM was stirred at RT for 1 h then ammonia was added and the mixture was stirred overnight. The mixture was diluted with DCM and washed with 2 N NaOH solution. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 0.040 g (82%) of IV-46.
  • IV-43 was prepared analogously to IV-46 except 152 was replaced with 150 to afford the corresponding 5-bromo-pyrimidine and in step 5 ammonia was replaced with 2-amino-propan-1-ol.
  • IV-42 was prepared analogously to IV-43 except step 5 was omitted.
  • IV-36 was prepared analogously except 166 was replaced with 4-(5-bromo-2-chloro-pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile.
  • IV-41 was prepared analogously to IV-36 except in step 5 ammonium was replaced with 2-dimethylamino-ethaneamine.
  • step 3 A mixture of 26a (2 mmol) and 4-amino-3,5-dimethylbenzonitrile (2 mmol) was heated neat in a sealed tube at 160° C. The reaction mixture became clear solution after 30 min and start to solidify as the product formed. After 6 h, TLC indicated that no starting material remained. The crude product was used in next step without further purification.
  • step 4 m-CPBA (6 mmol) was added portion wise to a solution of 174a (2 mmol) in DCM (15 mL) at 0° C. After the reaction mixture was warmed to RT and stirred for 3 h. The reaction mixture was quenched with Na 2 S 2 O 3 , diluted with DCM and washed sequentially with saturated Na 2 CO 3 , water, and brine. The organic phase was dried (Na 2 SO 4 ), filtered and the solvent was evaporated. The residue was purified by SiO 2 chromatography to afford 0.573 g (95% for two steps) of 174b.
  • step 5 A mixture of 172b (0.1 mmol), 174b (0.1 mmol) and DIPEA (0.2 mL) in DMSO (2 mL) was heated at 150° C. in a sealed tube overnight. After cooling, the mixture was concentrated and purified by prep-HPLC to afford 0.024 g (56%) of V-17.
  • 176b was carried out as described in step 1 of example 27 except 3-bromo-nitrobenzene was used in place of 162.
  • Step 2 was carried out as described in step 6 of example 5 to afford 176b.
  • 4-(2-Amino-5-bromo-pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (52) was prepared by condensation of 3,5-dimethyl-4-hydroxy-benzonitrile (177) and 150 as described in step 2 of example 24 except 146b was replaced by 177.
  • Condensation of 176b and 52 (step 3) was carried out by the procedure described in step 3 of example 24.
  • step 4 A mixture of 178a (2 mmol) and SnCl 2 (6 mmol) in EtOAc (10 mL) was refluxed overnight. The mixture was washed with Na 2 CO 3 solution (10 mL) and brine. The organic solution was dried (Na 2 SO 4 ), filtered and concentrated to afford 178b which was used in the next step without additional purification.
  • step 5 To a solution of 178b (0.1 mmol) and DIPEA (0.2 mL) in DCM (5 mL) was added acetyl chloride (0.12 mmol) at 0° C. The reaction mixture was warmed to RT and stirred for 1 h. The solvent was evaporated and the residue was purified by SiO 2 chromatography to afford 0.40 g (74% for 2 steps) of IV-39.
  • IV-38 was prepared in analogous fashion except in step 5, acetyl chloride was replaced with methanesulfonyl chloride.
  • step 1 To a solution of 180a (0.5 mmol) in DCM was added NBS (1 mmol). The resulting mixture was stirred overnight at RT. The reaction was quenched with water and the mixture was extracted with DCM. The organic extract was dried (Na 2 SO 4 ), filtered and solvents were evaporated. The residue was purified by SiO 2 chromatography to afford 0.169 g (85%) of 180b.
  • step 2 Condensation of 164b and 180b (step 2) was carried out by the procedure described in step 5 of example 28 to afford 182a. Steps 4 and 5 were carried out as described in steps 4 and 5 of example 27 except in step 5, ammonia was replaced by dimethylamine.
  • step 1 A mixture of 184a (2 mmol), NBS (2.2 mmol) and AIBN (100 mg) in CCl 4 (20 mL) was heated at reflux for 4 h. The mixture was cooled, filtered and the filtrate was concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 0.395 g (75%) of 184b.
  • step 2 A mixture of 32b (1 mmol), 184b (1 mmol) and TEA (0.1 mL) in DCM (2 mL) was stirred at RT overnight. The mixture was concentrated and purified by SiO 2 chromatography to afford 0.467 g (80%) of 186a.
  • Steps 3 and 4 were carried out by the procedures described in steps 4 and 5 of example 27 except in step 5, ammonia was replaced with N 1 ,N 1 -dimethyl-ethane-1,2-diamine.
  • step 1 To a solution of 188 (5 mmol) in DCM (20 mL) was added MCPBA (15 mmol) at RT and the reaction was stirred for 24 h. The precipitate was filtered and the filtrate was washed with Na2CO3. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified with SiO 2 chromatography to afford 0.066 g (92%) of 190.
  • step 1 Condensation of methyl 3-bromoacetate and 116 was carried out by the procedure described in step 1 of example 27.
  • step 2 To a solution of 192a (5 mmol) in THF (15 mL) at RT was added LiAlH 4 (5 mmol) portion wise. After stirring for 4 h, the reaction mixture was cooled to 0° and quenched by addition of water (0.25 mL), 15% NaOH (0.25 mL), water (1 mL). The precipitate was filtered and the filtrate was concentrated. The residue was purified by SiO 2 chromatography to afford 1.12 g (73%) of 192b.
  • step 3 Removal of the Boc-protecting group (step 3) was accomplished by the procedure described in step 6 of example 5 to afford 194. Condensation of 194 and 52 (step 4) was carried out by the procedure described for step 36 of example 24 to afford IV-37
  • step 1 Condensation of 3-bromo-styrene and 116 (step 1) was carried out by the procedure described in step 1 of example 27. Removal of the Boc-protecting group (step 2) was accomplished by the procedure described in step 6 of example 5 to afford 196b. Condensation of 196b and 52 (step 3) was carried out by the procedure described for step 3 of example 24 to afford 198a.
  • step 4 To a solution of 198a (0.5 mmol) and acetone (3 mL) at RT was added N-methyl-morpholine (1 mmol) and OsO 4 (5 mg). The mixture was stirred for 2 h, then Na 2 S 2 O 3 solution was added to quench the reaction and the mixture was stirred for 30 min. The mixture was partitioned between water and EtOAc. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford 0.269 g (40%) of IV-44.
  • step 1 To a solution of 164b (300 mg, 0.86 mmol) in THF (2 mL) in ice-water bath was added dropwise a solution of potassium hexamethyldisilazane (2 mL, 0.5 mol/L, 1 mmol, KHMDS). The mixture was stirred at 0° C. for 30 min. Methyl iodide (246 mg, 1.72 mmol) was added and the mixture was warmed to RT for 1 h. Aqueous NH 4 Cl was added to quench the reaction and the resulting mixture was extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 0.180 g (58%) of 200 as a yellow oil.
  • step 2 To a solution of 200 (180 mg, 0.5 mmol) in DCM (2 mL) was added TFA (0.5 mL) at RT. The mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was used in the next step without additional purification.
  • step 3 To the mixture of the TFA salt of 200 in DMSO (2 mL) was added DIPEA (646 mg, 5 mmol) followed by 52 (120 mg, 0.5 mmol). The mixture was heated at 120° C. overnight. The reaction mixture was cooled and poured into water then extracted with DCM. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 0.150 g (53.2%) of 202 as an oil.
  • step 4 To a solution of compound 202 (150 mg, 0.27 mmol) in MeOH (2 mL) was added 2M aqueous NaOH (0.52 mL, 1.04 mmol). The mixture was heated at 45° C. for 2 h. After removal of most of solvents in vacuo, the mixture was acidified with diluted aqueous HCl. The mixture was concentrated in vacuo and the residue was dissolved in DMF. The solution was purified by preparative HPLC to afford 0.067 g (46.2%) of IV-52.
  • step 1 To a solution of 164 (200 mg, 0.57 mmol) in DMSO (1 mL) under Ar was added of NaHCO 3 (2.4 mg, 0.03 mmol) followed by paraformaldehyde (22 mg, 0.69 mmol). The mixture was stirred at RT for 2 h then heated at 45° C. for 12 h. The mixture was cooled, poured into water and extracted with ether. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by SiO 2 chromatography to afford 0.130 g (62.5%) of 204 as oil.
  • Steps 2-4 were carried out by the procedure described in steps 24 of example 35 to afford IV-51.
  • step 1 To a solution of 164b (400 mg, 1.14 mmol) in THF (6.8 mL) at ⁇ 70° C. was added dropwise a solution of KHMDS (6.8 mL, 0.5 mol/L, 3.44 mmol). The mixture was stirred at ⁇ 70° C. for 20 min. N-fluorobenzenesulfinimide (1.08 g, 1.72 mmol, CASRN 133745-75-2) was added in portions and the mixture was stirred at ⁇ 70° C. for 30 min then warmed to ⁇ 10° C. for 10 min. Water was added to quench the reaction and the resulting mixture extracted with EtOAc. The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by SiO 2 chromatography to afford 0.380 g (86.7%) of 210 as an oil.
  • Steps 2-4 were carried out as described in steps 2-4 of example 35 to afford IV-55.
  • step 1 To a solution of 212a (626 mg, 1.14 mmol) in THF (2 mL) at ⁇ 70° C. was added dropwise a solution of KHMDS (5.5 mL, 0.5 mol/L, 2.74 mmol). The mixture was stirred at ⁇ 70° C. for 20 min. N-chlorosuccimide (335 mg, 2.51 mmol, NCS) was added portion wise then the mixture was stirred at ⁇ 70° C. for 30 min then warmed to 0° C. for 10 min. The reaction was quenched with aqueous NH 4 Cl and the resulting mixture extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford 0.680 g of 212b which was used directly in next step.
  • KHMDS 5.5 mL, 0.5 mol/L, 2.74 mmol
  • step 2 To a solution of compound 212b (230 mg, 0.37 mmol) in MeOH (2 mL) was added aqueous NaOH (1.8 mL, 2 mol/L, 3.6 mmol). The mixture was stirred at RT the cooled to RT. After removal of most of solvents in vacuo, the mixture was acidified with diluted aqueous HCl and filtered. The resulting solid is unstable and was used directly in the next step.
  • step 3 To a solution of 214a (120 mg, 0.21 mmol) from step 2 in MeOH (2 mL) at RT was added in portions NaBH 4 (75 mg, 2.1 mmol). The mixture was stirred at RT for 30 min. Aqueous HCl was added to quench the reaction and the resulting solution was concentrated in vacuo and the product was purified by preparative HPLC to afford 0.045 g (38.9%) of IV-54.
  • step 1 To a solution of 216a (1.19 g, 5 mmol) in CCl 4 (30 mL) was added NBS (1.08 g, 6 mmol) followed by benzoyl peroxide (catalytic quantity). The mixture was heated at 80° C. overnight. Then the mixture was cooled, filtered and the solid washed with hexane. The combined filtrates were concentrated in vacuo to afford 1.58 g (100%) of 216b as yellow oil.
  • step 2 To a sodium methoxide-MeOH solution from Na metal (0.44 g, 18.9 mmol) and MeOH (50 mL) was added 216b (4.86 g, 15.8 mmol) and the mixture was heated at 80° C. for 30 min. The resulting mixture was cooled and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 2.5 g (62%) of 216c as an oil.
  • step 3 To a mixture of 216c (2.5 g, 9.6 mmol), CuI (164 mg, 0.96 mmol), L-proline (221 mg, 1.92 mg) and K 2 CO 3 (2.65 g, 19.2 mmol) in DMSO (40 mL) was added 116 (2.7 g, 13.5 mmol). The mixture was heated at 100° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by SiO 2 chromatography to afford 0.670 g (18.4%) of compound 218a.
  • steps 4-6 Removal of the Boc-protecting group was accomplished by the procedure described in step 3 of example 24 to afford 218b.
  • Condensation of 52 and 218b and subsequent hydrolysis of the ester to afford IV-53 was carried out as described in steps 3 and 4 of example 34.
  • IV-56 and IV-57 were prepared by an analogous route except 5-bromo-2,4-dichloro-pyrimidine was replaced with 2,4,5-trichloro-pyrimidine and 2,4-dichloro-5-methyl-pyrimidine respectively.
  • RNA-dependent DNA polymerase activity was measured using a biotinylated primer oligonucleotide and tritiated dNTP substrate. Newly synthesized DNA was quantified by capturing the biotinylated primer molecules on streptavidin coated Scintillation Proximity Assay (SPA) beads (Amersham).
  • the sequences of the polymerase assay substrate were: 18 nt DNA primer, 5′-Biotin/GTC CCT GTT CGG GCG CCA-3′; 47 nt RNA template, 5′-GGG UCU CUC UGG UUA GAC CAC UCU AGC AGU GGC GCC CGA ACA GGG AC-3′.
  • the biotinylated DNA primer was obtained from the Integrated DNA Technologies Inc. and the RNA template was synthesized by Dharmacon.
  • the reactions contained 5 ⁇ l of serial compound dilutions in 100% DMSO for IC 50 determination and the final concentrations of DMSO were 10%. Reactions were initiated by the addition of 301 of the HIV-RT enzyme (final concentrations of 1-3 nM). Protein concentrations were adjusted to provide linear product formation for at least 30 min of incubation. After incubation at 30° for 30 min, the reaction was quenched by addition of 50 ⁇ l of 200 mM EDTA (pH 8.0) and 2 mg/ml SA-PVT SPA beads (Amersham, RPNQ0009, reconstituted in 20 mM Tris-HCl, pH 8.0, 100 mM EDTA and 1% BSA). The beads were left to settle overnight and the SPA signals were counted in a 96-well top counter-NXT (Packard). IC 50 values were obtained by sigmoidal regression analysis using GraphPad Prism 3.0 (GraphPad Software, Inc.).
  • the sensitivity of a wild-type laboratory strain HIV-1HXB2 to described compounds was determined by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) cell viability assay with MT-4 cells (R. Pauwels et al., “Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds,” J. Virological Methods 1988 20:309-321). Briefly, MT-4 cells were incubated with virus (MOI 0.0001) for 1 h at 37° C.
  • virus MOI 0.0001
  • compositions of the subject compounds for administration via several routes were prepared as described in this Example.
  • composition for Oral Administration (A) Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%
  • the ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.
  • composition for Oral Administration Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%
  • the ingredients are combined and granulated using a solvent such as methanol.
  • the formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.
  • Composition for Oral Administration Ingredient % wt./wt. Active compound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml
  • the ingredients are mixed to form a suspension for oral administration.
  • Parenteral Formulation (D) Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to make isotonic Water for injection to 100 ml
  • the active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.
  • Suppository Formulation (E) Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%
  • the ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US12/001,947 2006-12-13 2007-12-13 Non-nucleoside reverse transcriptase inhibitors Expired - Fee Related US7998969B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/001,947 US7998969B2 (en) 2006-12-13 2007-12-13 Non-nucleoside reverse transcriptase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87467306P 2006-12-13 2006-12-13
US12/001,947 US7998969B2 (en) 2006-12-13 2007-12-13 Non-nucleoside reverse transcriptase inhibitors

Publications (2)

Publication Number Publication Date
US20080146595A1 US20080146595A1 (en) 2008-06-19
US7998969B2 true US7998969B2 (en) 2011-08-16

Family

ID=39381919

Family Applications (1)

Application Number Title Priority Date Filing Date
US12/001,947 Expired - Fee Related US7998969B2 (en) 2006-12-13 2007-12-13 Non-nucleoside reverse transcriptase inhibitors

Country Status (17)

Country Link
US (1) US7998969B2 (zh)
EP (1) EP2089384B1 (zh)
JP (1) JP5415957B2 (zh)
KR (1) KR101475091B1 (zh)
CN (1) CN101553483B (zh)
AR (1) AR064221A1 (zh)
AU (1) AU2007332654B2 (zh)
BR (1) BRPI0720436A2 (zh)
CA (1) CA2671478C (zh)
CL (1) CL2007003565A1 (zh)
ES (1) ES2550152T3 (zh)
IL (1) IL199152A (zh)
MX (1) MX2009005881A (zh)
PE (1) PE20081509A1 (zh)
RU (1) RU2469032C2 (zh)
TW (1) TW200833681A (zh)
WO (1) WO2008071587A2 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179164A1 (en) * 2009-01-14 2010-07-15 Hui Li 2,4-pyrimidinediamine compounds for treatment of inflammatory disorders

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009115583A1 (en) 2008-03-20 2009-09-24 Boehringer Ingelheim International Gmbh Regioselective preparation of substituted pyrimidines
UY31714A (es) 2008-03-20 2009-11-10 Boehringer Ingelheim Int Preparación selectiva de pirimidinas sustituidas
TW201024281A (en) 2008-11-24 2010-07-01 Boehringer Ingelheim Int New compounds
AR074210A1 (es) 2008-11-24 2010-12-29 Boehringer Ingelheim Int Derivados de pirimidina como inhibidores de ptk2-quinasa
AR076024A1 (es) * 2009-04-03 2011-05-11 Schering Corp Derivados de heterociclos biciclicos puenteados y metodos de uso de los mismos
US8153790B2 (en) 2009-07-27 2012-04-10 Krizmanic Irena Process for the preparation and purification of etravirine and intermediates thereof
US8933227B2 (en) * 2009-08-14 2015-01-13 Boehringer Ingelheim International Gmbh Selective synthesis of functionalized pyrimidines
WO2011018517A1 (en) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives
GR1007010B (el) 2009-10-08 2010-10-07 Χημικα Και Βιοφαρμακευτικα Εργαστηρια Πατρων Αε (Cbl-Patras), Ινσουλινοειδη πεπτιδια
CN101723904B (zh) * 2009-11-26 2012-02-08 复旦大学 4-氰基二芳基嘧啶类衍生物及其制备方法和用途
CN103140474A (zh) * 2010-07-02 2013-06-05 吉里德科学公司 治疗aids的萘-2-基乙酸衍生物
CN103209963A (zh) 2010-07-02 2013-07-17 吉里德科学公司 作为hiv抗病毒化合物的2-喹啉基-乙酸衍生物
BR112013027096A2 (pt) 2011-04-21 2016-12-27 Gilead Sciences Inc compostos de benzotiazol e seu uso farmacêutico
CN102285969B (zh) * 2011-06-28 2013-06-19 山东大学 N-1-取代哌啶-4-芳胺类衍生物及其制备方法与应用
CN102382062B (zh) * 2011-08-01 2014-08-13 复旦大学 一种环烷基芳基嘧啶类衍生物及其制备方法和用途
WO2013059572A1 (en) 2011-10-19 2013-04-25 Assia Chemical Industries Ltd. Process for the preparation of etravirine and intermediates in the synthesis thereof
WO2013062028A1 (ja) 2011-10-25 2013-05-02 塩野義製薬株式会社 Ｈｉｖ複製阻害剤
WO2013103738A1 (en) 2012-01-04 2013-07-11 Gilead Sciences, Inc. Napthalene acetic acid derivatives against hiv infection
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
MD20140063A2 (ro) 2012-04-20 2014-12-31 Gilead Sciences, Inc. Derivaţi de acid benzotiazol-6-il acetic şi utilizarea acestora pentru tratarea unei infecţii HIV
CA2884582C (en) * 2012-10-26 2020-10-27 Asahi Glass Co Ltd Method for producing difluoro ester compound
CN102964295B (zh) * 2012-12-17 2014-08-20 寿光富康制药有限公司 一种2-取代-4-（哌啶基甲基）吡啶的制备方法
TW201441197A (zh) 2013-01-31 2014-11-01 Shionogi & Co Ｈｉｖ複製抑制劑
CN103523533A (zh) * 2013-07-25 2014-01-22 上海董奥机械科技有限公司 一种用于pet空瓶气流输送的装置
CN110066273A (zh) * 2019-06-05 2019-07-30 山东大学 一种含三氮唑环的单芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用
CN110407812B (zh) * 2019-07-31 2020-08-25 武汉工程大学 一种吲唑哌啶嘧啶类衍生物及其制备方法和用途
CN111285859B (zh) * 2020-04-02 2021-07-02 山东大学 一类以hiv-1逆转录酶为靶点的2,4,5-三取代嘧啶类化合物及其制备方法与应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000003998A1 (en) 1998-07-17 2000-01-27 Novirio Pharmaceuticals Limited Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them
WO2003016306A1 (en) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Hiv inhibiting pyrimidines derivatives
WO2006035068A2 (en) 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-carbo- or heterocyclic substituted pyrimidines
WO2006035067A2 (en) 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-heterocyclyl pyrimidines
WO2006035369A2 (en) 2004-09-28 2006-04-06 Koninklijke Philips Electronics N.V. Current-mode controlled dc-dc converter
WO2006045828A1 (en) 2004-10-29 2006-05-04 Tibotec Pharmaceuticals Ltd. Hiv inhibiting bicyclic pyrimidine derivatives
WO2006087387A1 (en) 2005-02-18 2006-08-24 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 2-(4-cyanophenylamino) pyrimidine oxide derivatives
WO2006094930A1 (en) 2005-03-04 2006-09-14 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 2-(4-cyanophenyl)-6-hydroxylaminopyrimidines

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4949314A (en) 1966-08-16 1990-08-14 The United States Of America As Represented By The Secretary Of The Navy Method and means for increasing echo-ranging-search rate
US4211771A (en) 1971-06-01 1980-07-08 Robins Ronald K Treatment of human viral diseases with 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
US4518584A (en) 1983-04-15 1985-05-21 Cetus Corporation Human recombinant interleukin-2 muteins
GB8327880D0 (en) 1983-10-18 1983-11-16 Ajinomoto Kk Saccharomyces cerevisiae
US4530787A (en) 1984-03-28 1985-07-23 Cetus Corporation Controlled oxidation of microbially produced cysteine-containing proteins
US4604377A (en) 1984-03-28 1986-08-05 Cetus Corporation Pharmaceutical compositions of microbially produced interleukin-2
US4569790A (en) 1984-03-28 1986-02-11 Cetus Corporation Process for recovering microbially produced interleukin-2 and purified recombinant interleukin-2 compositions
IL76360A0 (en) 1984-09-26 1986-01-31 Takeda Chemical Industries Ltd Mutual separation of proteins
US4752585A (en) 1985-12-17 1988-06-21 Cetus Corporation Oxidation-resistant muteins
US4748234A (en) 1985-06-26 1988-05-31 Cetus Corporation Process for recovering refractile bodies containing heterologous proteins from microbial hosts
AU622926B2 (en) 1988-09-09 1992-04-30 Nippon Kayaku Kabushiki Kaisha Pyrimidine or purine cyclobutane derivatives
US5204466A (en) 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US5925643A (en) 1990-12-05 1999-07-20 Emory University Enantiomerically pure β-D-dioxolane-nucleosides
US5349068A (en) 1992-04-15 1994-09-20 Sterling Winthrop Inc. 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
US5464933A (en) 1993-06-07 1995-11-07 Duke University Synthetic peptide inhibitors of HIV transmission
JP3398152B2 (ja) * 1993-10-12 2003-04-21 ブリストル‐マイヤーズ・スクイブ・ファーマ・カンパニー １ｎ−アルキル−ｎ−アリールピリミジンアミンおよびその誘導体
US5489697A (en) 1994-08-03 1996-02-06 Medichem Research, Inc. Method for the preparation of (+)-calanolide A and intermediates thereof
EP0809511A1 (en) 1995-02-16 1997-12-03 F. Hoffmann-La Roche Ag Inhibition of angiogenesis using interleukin-12
MY115461A (en) 1995-03-30 2003-06-30 Wellcome Found Synergistic combinations of zidovudine, 1592u89 and 3tc
IL117574A0 (en) 1995-04-03 1996-07-23 Bristol Myers Squibb Co Processes for the preparation of cyclobutanone derivatives
US7217714B1 (en) 1998-12-23 2007-05-15 Agouron Pharmaceuticals, Inc. CCR5 modulators
WO2000063184A1 (de) 1999-04-16 2000-10-26 Lonza Ag Verfahren zur herstellung von 2-(alkylthio)-4-chlorpyrimidinen
ES2246233T3 (es) 1999-05-04 2006-02-16 Schering Corporation Derivados de piperidina utiles como antagonistas de ccr5.
DE60021370C5 (de) 1999-05-04 2007-11-08 Schering Corp. Piperazinderivate verwendbar als ccr5 antagonisten
GB0005642D0 (en) 2000-03-10 2000-05-03 Astrazeneca Uk Ltd Chemical compounds
GB0011838D0 (en) 2000-05-17 2000-07-05 Astrazeneca Ab Chemical compounds
SI1284974T1 (en) 2000-05-26 2004-08-31 Pfizer Inc. Triazolyl tropane derivatives as ccr5 modulators
US6620586B2 (en) 2001-02-20 2003-09-16 Applied Gene Technologies, Inc. Methods and compositions for analyzing nucleic acids
DE60236418D1 (de) 2001-03-19 2010-07-01 Dainippon Sumitomo Pharma Co Arylsubstituierte alicyclische verbindung und diese enthaltende medizinische zusammensetzung
GB0107228D0 (en) 2001-03-22 2001-05-16 Astrazeneca Ab Chemical compounds
GB0108046D0 (en) 2001-03-30 2001-05-23 Astrazeneca Ab Chemical compounds
GB0127547D0 (en) 2001-11-16 2002-01-09 Astrazeneca Ab Chemical compounds
SE0200919D0 (sv) 2002-03-25 2002-03-25 Astrazeneca Ab Chemical compounds
AR039540A1 (es) * 2002-05-13 2005-02-23 Tibotec Pharm Ltd Compuestos microbicidas con contenido de pirimidina o triazina
SE0202483D0 (sv) 2002-08-21 2002-08-21 Astrazeneca Ab Chemical compounds
EP1571146A4 (en) * 2002-12-10 2010-09-01 Ono Pharmaceutical Co NITROGENIC HETEROCYCLIC COMPOUNDS AND THEIR MEDICAL USE
AR042628A1 (es) 2002-12-20 2005-06-29 Astrazeneca Ab Derivados de piperidina como moduladores del receptor ccr5
CA2554671A1 (en) 2004-02-10 2005-08-18 F.Hoffmann-La Roche Ag Chemokine ccr5 receptor modulators
US20050282793A1 (en) 2004-05-21 2005-12-22 Ralf Wyrwa Steroid prodrugs with androgenic action
DE602005004144T2 (de) 2004-06-09 2009-01-29 F. Hoffmann-La Roche Ag Octahydropyrroloä3,4-cüpyrrolderivate und deren verwendung als antivirale mittel
US20050288502A1 (en) 2004-06-25 2005-12-29 Andersen Denise L Substituted heterocyclic compounds and methods of use
WO2006037117A1 (en) * 2004-09-27 2006-04-06 Amgen Inc. Substituted heterocyclic compounds and methods of use
AU2006262016A1 (en) 2005-06-28 2007-01-04 Merck & Co., Inc. Non-nucleoside reverse transcriptase inhibitors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000003998A1 (en) 1998-07-17 2000-01-27 Novirio Pharmaceuticals Limited Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them
WO2003016306A1 (en) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Hiv inhibiting pyrimidines derivatives
WO2006035369A2 (en) 2004-09-28 2006-04-06 Koninklijke Philips Electronics N.V. Current-mode controlled dc-dc converter
WO2006035068A2 (en) 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-carbo- or heterocyclic substituted pyrimidines
WO2006035067A2 (en) 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-heterocyclyl pyrimidines
WO2006045828A1 (en) 2004-10-29 2006-05-04 Tibotec Pharmaceuticals Ltd. Hiv inhibiting bicyclic pyrimidine derivatives
WO2006087387A1 (en) 2005-02-18 2006-08-24 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 2-(4-cyanophenylamino) pyrimidine oxide derivatives
WO2006094930A1 (en) 2005-03-04 2006-09-14 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 2-(4-cyanophenyl)-6-hydroxylaminopyrimidines

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
Brugel, T.A., et. al. "Development of N-2,4-pyrimidine-N-phenyl-N′-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-α) synthesis. Part 1," Bioorganic & Medicinal Chemistry Letters (2006) vol. 16, pp. 3510-3513.
Brugel, T.A., et. al. "Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1," Bioorganic & Medicinal Chemistry Letters (2006) vol. 16, pp. 3510-3513.
Das, K., et. al. "Roles of Conformational and Positional Adaptability in Structure-Based Design of TMC125-R165335 (Etravirine) and Related Non-nucleoside reverse Transcriptase Inhibitors that are Highly Potent and Effective Against Wild-type and Drug-Resistant HIV-1 Variants," J. Med. Chem. (2004) vol. 47, pp. 2550-2560.
Guillemont, J., et. al. "Synthesis of Novel Diarylpyrimidine Analogues and Their Antiviral Activity against Human Immunodeficiency Virus Type 1," J. Med. Chem. (2005) vol. 48, pp. 2072-2079.
Janssen, P.A., et. al. "In Search of a Novel Anti-HIV Drug: Multidisciplinary Coordination in the Discovery of 4-[[4-[[4-[(1E)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (R278474, Rilpivirine)," J. Med. Chem. (2005) vol. 48, pp. 1901-1909.
Marcus et al., PubMed Abstract (Intervirology 45(4-6):260-6) 2002. *
Miles, Medline Abstract (Community Pract, vol. 78, Issue 8, pp. 292-294) Aug. 2005. *
van Heeswijk et al., PubMed Abstract (Antivir Ther. 6(4):201-29) Dec. 2001. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179164A1 (en) * 2009-01-14 2010-07-15 Hui Li 2,4-pyrimidinediamine compounds for treatment of inflammatory disorders
US8334297B2 (en) * 2009-01-14 2012-12-18 Rigel Pharmaceuticals Inc. 2,4-pyrimidinediamine compounds for treatment of inflammatory disorders

Also Published As

Publication number Publication date
CL2007003565A1 (es) 2008-07-04
EP2089384B1 (en) 2015-08-05
KR20090087512A (ko) 2009-08-17
CN101553483A (zh) 2009-10-07
EP2089384A2 (en) 2009-08-19
AR064221A1 (es) 2009-03-18
CA2671478A1 (en) 2008-06-19
RU2469032C2 (ru) 2012-12-10
JP5415957B2 (ja) 2014-02-12
WO2008071587A2 (en) 2008-06-19
KR101475091B1 (ko) 2014-12-22
JP2010513240A (ja) 2010-04-30
IL199152A (en) 2015-11-30
CA2671478C (en) 2015-02-17
MX2009005881A (es) 2009-06-12
US20080146595A1 (en) 2008-06-19
BRPI0720436A2 (pt) 2014-01-07
AU2007332654A1 (en) 2008-06-19
ES2550152T3 (es) 2015-11-04
WO2008071587A3 (en) 2008-07-31
RU2009126624A (ru) 2011-01-20
TW200833681A (en) 2008-08-16
PE20081509A1 (es) 2008-10-24
CN101553483B (zh) 2013-04-17
AU2007332654B2 (en) 2013-06-20

Similar Documents

Publication Publication Date Title
US7998969B2 (en) Non-nucleoside reverse transcriptase inhibitors
US7754919B2 (en) Non-nucleoside reverse transcriptase inhibitors
US7388111B2 (en) Non-nucleoside reverse transcriptase inhibitors
US7906540B2 (en) Non-nucleoside reverse transcriptase inhibitors
ES2360893T3 (es) Inhibidores no nucleósidos de la transcriptasa inversa.
US20070191335A1 (en) Heterocylic antiviral compounds
EP1937651B1 (en) Nnrt inhibitors
US20070191406A1 (en) Heterocyclic antiviral compounds
US20080020981A1 (en) Non-nucleoside reverse transcriptase inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: ROCHE PALO ALTO LLC, CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KERTESZ, DENIS JOHN;BROTHERTON-PLEISS, CHRISTINE E.;YANG, MINMIN;REEL/FRAME:020691/0590;SIGNING DATES FROM 20080131 TO 20080227

Owner name: ROCHE PALO ALTO LLC, CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KERTESZ, DENIS JOHN;BROTHERTON-PLEISS, CHRISTINE E.;YANG, MINMIN;SIGNING DATES FROM 20080131 TO 20080227;REEL/FRAME:020691/0590

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20190816